Glucocorticoids, Inhaled Therapeutic Class Review (TCR)

Transcription

1 Glucocorticoids, Inhaled Therapeutic Class Review (TCR) July 31, 2015 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to [email protected]. July 2015

2 FDA-APPROVED INDICATIONS Drug Manufacturer Indication(s) Glucocorticoids beclomethasone HFA Teva Maintenance treatment of asthma as prophylactic therapy inhalation aerosol (QVAR ) 1 (see indicated ages below for each product) budesonide inhalation powder (Pulmicort Flexhaler ) 2 budesonide inhalation suspension (Pulmicort Respules ) 3 ciclesonide inhalation aerosol (Alvesco ) 4 flunisolide HFA (Aerospan ) 5 fluticasone furoate inhalation powder (Arnuity Ellipta) 6 fluticasone propionate inhalation aerosol (Flovent HFA ) 7 fluticasone propionate inhalation powder (Flovent Diskus ) 8 mometasone furoate inhalation powder (Asmanex Twisthaler) 9 mometasone furoate inhalation aerosol (Asmanex HFA) 10 AstraZeneca AstraZeneca, generic Sunovion Acton GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline Merck Merck For asthma patients requiring systemic corticosteroid administration to reduce or eliminate the need for oral systemic corticosteroids Indicated Ages QVAR is for use in patients age five years and older Pulmicort Flexhaler is for use in patients age six years and older Pulmicort Respules are used in patients age 12 months to eight years Flovent HFA and Flovent Diskus are for use in patients age four years and older Asmanex is for use in patients age four years and older Aerospan is for use in patients six years and older Alvesco, Arnuity Ellipta, and Asmanex HFA are for adult and adolescent patients 12 years of age and older Page 2

3 FDA-Approved Indications (continued) budesonide / formoterol inhalation aerosol (Symbicort ) 11 Glucocorticoid/Bronchodilator Combinations Drug Manufacturer Indication(s) AstraZeneca Treatment of asthma in patients 12 years of age and older Maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and emphysema fluticasone furoate /vilanterol (Breo Ellipta ) 12 GlaxoSmithKline Long-term, once, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema To reduce exacerbations of COPD in patients with a history of exacerbations Treatment of asthma in patients 18 years of age and older fluticasone propionate / salmeterol inhalation aerosol (Advair HFA) 13 fluticasone propionate / salmeterol inhalation powder (Advair Diskus) 14 GlaxoSmithKline Treatment of asthma in patients 12 years of age and older GlaxoSmithKline Treatment of asthma in patients four years of age and older Maintenance treatment of airflow obstruction in COPD including chronic bronchitis and emphysema (250 mcg/50 mcg only) To reduce COPD exacerbations in patients with a history of exacerbations (250 mcg/50 mcg only) mometasone / formoterol Merck Treatment of asthma in patients 12 years of age and older inhalation aerosol (Dulera ) 15 The manufacturing, sale, and dispensing of chlorofluorocarbon (CFC) containing inhalers has been phased out by the United States (US) Food and Drug Administration (FDA) to comply with the Montreal Protocol. 16 Inhalers utilizing an alternative inhalant technology, as shown above, have emerged to meet the needs of patients left by the void. 17 For asthma therapy, the combination products budesonide/formoterol (Symbicort), fluticasone propionate/salmeterol (Advair Diskus, Advair HFA), mometasone/formoterol (Dulera), and fluticasone furoate/vilanterol (Breo Ellipta) should only be prescribed for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid (ICS), or whose disease severity clearly warrants initiation of treatment with both an ICS and a long-acting beta 2 agonist (LABA). These combination products are not indicated for the relief of acute bronchospasms. OVERVIEW Asthma Prevalence of asthma in the United States continues to rise. In 2010, total asthma prevalence was estimated to be 8.4% of the population, or approximately 25.7 million Americans. 18 Further, the National Health Statistics Report shows that asthma appears to disproportionately affect minority groups, females, children, and individuals of low socioeconomic status which can place significant pressure on public health systems. 19 The National Asthma Education and Prevention Program (NAEPP) has defined asthma as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. 20 In susceptible individuals, inflammation may cause recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. These episodes are usually associated with Page 3

4 airflow obstruction that is often reversible, either spontaneously or with treatment. The inflammation also causes an increase in bronchial hyper-responsiveness to a variety of stimuli. Studies have demonstrated the efficacy of inhaled corticosteroids (ICS) in improving lung function, reducing symptoms, reducing frequency and severity of exacerbations, and improving the quality of life (QoL) of patients with asthma. 21,22,23,24,25 The 2007 National Heart, Lung, and Blood Institute, National Institutes of Health (NHLBI, NIH), and the 2015 Global Initiative for Asthma (GINA) state that inhaled glucocorticoids are currently the most effective anti-inflammatory medications for the treatment of persistent asthma. 26,27 The 2015 GINA guidelines offer a control-based management plan to adjust treatment in a continuous cycle of assessment, treatment, and review of the patient s response as it relates to symptom control, future risk of exacerbations, and side effects. 28 Equally important in this process is identifying the patient s own goals regarding their asthma management to ensure improved outcomes. During this continuous cycle, a stepwise treatment approach is offered to achieve control using the patient s current level of control as the baseline. If the patient is not controlled on the current regimen, treatment should be stepped up until control is achieved. If control is maintained for at least three months on the current regimen, treatment can be stepped down to the lowest step and dosage that maintains control. A combination ICS/long-acting beta 2 -agonist (LABA) product is the preferred step-up treatment for adults and adolescents currently on a low dose ICS who continue to have persistent symptoms/exacerbations. The risk of exacerbations can be reduced in adolescents and adults who are using other alternative therapies with treatment of a low dose ICS/formoterol (with beclomethasone or budesonide). For children (six to 11 years of age) with persistent symptoms, an increased ICS dose is preferred over use of an ICS/LABA agent. Page 4

5 Assessment of Asthma Control from 2015 GINA Guidelines 29 Characteristic Well Controlled (all of the following) Partly Controlled (any present in past week) Uncontrolled A. Assessment of symptom control (preferably over four weeks) Daytime symptoms None (Twice or less per week) Limitations of activities None Any Nocturnal symptoms/awakening None Any Need for reliever/rescue treatment None (Twice or less per week) More than twice per week More than twice per week B. Assessment of future risk (risk of exacerbations, fixed airflow limitation, side effects) Three or more features of partly controlled asthma in any week Independent risk factors for exacerbations include (one or more of these risk factors increases risk for exacerbations despite well controlled symptoms): Uncontrolled asthma symptoms, excessive short-acting beta 2- agonist (SABA) use, inadequate ICS, frequent exacerbations in the past, any admission to critical care for asthma, low forced expiratory volume in one second (FEV 1 ), exposure to cigarette smoke/allergens, major psychological or socioeconomic problems, comorbidities, pregnancy, and sputum or blood eosinophilia Fixed air flow limitation risk factors include: Lack of ICS treatment, tobacco/chemical/occupational exposures, and low initial FEV 1 Risk factors for medication side effects include: Frequent oral corticosteroid use, long-term/high dose ICS, taking P450 inhibitors, and poor inhaler technique FEV 1 = forced expiratory volume in one second; ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; SABA = short acting beta 2 -agonist Page 5

6 Stepwise Approach to Asthma Control from 2015 GINA Guidelines 30 Step 1 Step 2 Step 3 Adults and Children Six Years of Age And Older As-needed reliever medication Recommended: SABA Alternative Controller: consider low dose ICS One controller AND an as-needed reliever medication Preferred controller: low-dose ICS + SABA Alternative controllers: leukotriene modifier or low dose theophylline* One or two controllers and an as-needed reliever medication Preferred for adolescents and adults: low-dose ICS AND a LABA as maintenance plus as-needed SABA Preferred for children six to 11 years of age: medium dose ICS + as-needed SABA Alternative controllers: medium- or high-dose ICS, OR low-dose ICS + leukotriene modifier, OR Low-dose ICS + sustained-release theophylline* Two or more Scontrollers AND an as-needed reliever medication Preferred t for adolescents and adults: low dose ICS/formoterol as maintenance + reliever treatment; OR medium-dose e ICS + LABA plus as-needed SABA Preferred p for children six to 11 years of age: referral to expert for assessment and advice Alternative controllers: 4 For adults and adolescents: high-dose ICS + LABA may be considered as trial for three to six months when medium-dose ICS/LABA and/or a third controller (e.g., leukotriene modifier OR sustained release theophylline*) Higher level Sof care and/or add-on treatment In addition t to Step 4 treatment add either: e Alternative controller: oral corticosteroids (lowest dose) p Anti-IgE treatment (omalizumab [Xolair ]) 5 * For children six to 11 years of age, theophylline is not recommended. ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; SABA = short acting beta 2 -agonist The NAEPP Expert Panel Report-3 (EPR-3) report released in 2007 also recommends a similar classification of asthma severity and control, to guide in the initiation and adjustment of therapy, respectively. 31 Asthma severity and control are defined in terms of two domains, impairment and risk. The distinction between these domains emphasizes the need to consider separately, asthma s effects on quality of life and functional capacity on an ongoing basis (e.g., in the present), along with risks for adverse events, such as exacerbations and progressive loss of pulmonary function. Page 6

7 Stepwise Approach for Managing Persistent Asthma from the NAEPP Expert Panel Report-3 32 Severity of Asthma Step 1 Intermittent Asthma Step 2 Persistent Asthma Step 3 Persistent Asthma Step 4 Persistent Asthma Step 5 Persistent Asthma Step 6 Persistent Asthma No medications needed SABA as needed Adults and Children 12 Years Low-dose ICS Alternative: cromolyn, LTRA, nedocromil, or theophylline Low-dose ICS + LABA OR Medium-dose ICS Alternative: Low-dose ICS and one of the following: LTRA, theophylline, or zileuton Medium-dose ICS + LABA Alternative: Medium-dose ICS and one of the following: LTRA, theophylline, or zileuton (Zyflo) High-dose ICS + LABA Consider omalizumab for patients who have allergies High-dose ICS + LABA + oral corticosteroid Consider omalizumab for patients who have allergies ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; LTRA = leukotriene receptor antagonist or leukotriene modifier; SABA = short acting beta 2 -agonist All asthma patients should have a short-acting beta 2 -agonist inhaler for use on an as-needed basis. Page 7

8 Stepwise Approach for Managing Persistent Asthma from the NAEPP Expert Panel Report-3 33 Severity of Asthma Children from Birth to Four Years of Age Step 1 Intermittent Asthma Step 2 Persistent Asthma Step 3 Persistent Asthma Step 4 Persistent Asthma Step 5 Persistent Asthma Step 6 Persistent Asthma No medications needed SABA as needed Now-dose ICS Alternative: cromolyn or montelukast Children Five to 11 Years of Age No medications needed SABA as needed Low-dose ICS Alternative: cromolyn, LTRA, nedocromil, or theophylline Medium-dose ICS Low-dose ICS + LABA OR LTRA OR theophylline OR Medium-dose ICS Medium-dose ICS + LABA OR montelukast High-dose ICS + LABA OR montelukast High-dose ICS + LABA OR montelukast (Singulair ) + oral corticosteroid Medium-dose ICS + LABA Alternative: medium-dose ICS + LTRA OR theophylline High-dose ICS + LABA Alternative: high-dose ICS + LTRA OR theophylline High-dose ICS + LABA + oral corticosteroid Alternative: high-dose ICS + LTRA OR theophylline + oral corticosteroids ICS = inhaled corticosteroid; LABA = long acting beta 2 -agonist; LTRA = leukotriene receptor antagonist or leukotriene modifier; SABA = short acting beta 2 -agonist COPD The 2015 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines define chronic obstructive pulmonary disease (COPD) as a preventable and treatable disease in which its pulmonary component is characterized by airflow limitation that is not fully reversible. 34 The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. It is estimated that the number of Americans with a COPD diagnosis exceeds 15 million. 35 Bronchodilator therapy (e.g., beta 2 -agonists, anticholinergics, and methylxanthines) is central to symptom management in COPD, and the inhaled route is preferred. The 2015 GOLD guidelines reference that a subset of LABAs (e.g., formoterol and salmeterol) have demonstrated improvement in FEV 1 and quality of life, as well as decreasing dyspnea and exacerbation and hospitalization rates in COPD patients. 36 However, no significant benefit on mortality or the rate of lung function decline has been demonstrated. While most studies indicate that the existing medications for COPD do not modify the long-term decline in lung function, there is limited evidence that regular treatment with LABAs, inhaled corticosteroids (ICS), and their combination can decrease the rate of decline of lung function. Therefore, pharmacotherapy for COPD is mainly used to decrease symptoms and/or complications. Page 8

9 The GOLD guidelines classify COPD patients into four groups based on risk for exacerbation and symptom severity. Patients in Group A are considered to have a low risk for exacerbation and less COPD symptoms; Group B patients have low exacerbation risk and more symptoms; Group C patients are at high risk for COPD exacerbations, but have less symptoms; and Group D patients are at high risk for exacerbation and have more symptoms. First choice therapy for patients in Group A is as-needed use of a short-acting bronchodilator. Long-acting bronchodilators are recommended for patients who fit Group B description. The GOLD guidelines recommend the addition of ICS to long-acting bronchodilator therapy, such as LABA, for patients with severe to very severe COPD represented as Group C and D patients. 37 An ICS in combination with a LABA is more effective than the individual components in reducing exacerbations and improving lung function and health status. Direct head-to-head studies of combination ICS/LABA and ICS/long-acting anticholinergics are widely absent making comparison and differentiation difficult. 38 A Cochrane Review suggests no significant difference in mortality or lung function (FEV 1 ) between tiotropium, a long-acting anticholinergic agent, and LABAs; however, statistically significant differences in the number of patients experiencing one or more exacerbations were seen in favor of tiotropium, particularly when compared against salmeterol (Odds ratio [OR] 0.86; 95% confidence interval [CI], ). 39 Tiotropium and related anticholinergic products are reviewed under a separate Therapeutic Class Review. PHARMACOLOGY 40,41,42,43,44,45,46,47,48,49 Corticosteroids suppress the cytokine generation, recruitment of airway eosinophils, and release of inflammatory mediators. These agents thereby block late-phase reaction to allergens, reduce airway hyperresponsiveness, and inhibit inflammatory cell migration and activation. 50 Because systemic corticosteroids have a high incidence of adverse reactions, inhaled corticosteroids (ICS) are preferred for asthma. Advair is a combination product containing a long-acting beta 2 -agonist (LABA), salmeterol DPI (Serevent) and a corticosteroid, fluticasone (as propionate). Breo Ellipta also contains the ICS fluticasone (as furoate), as well as the LABA vilanterol. Symbicort is a combination product containing a LABA, formoterol, and an ICS, budesonide. Dulera is a combination product containing the LABA, formoterol and the ICS, mometasone. Formoterol, vilanterol, and salmeterol selectively bind to the beta 2 -receptors in the bronchial smooth muscle, leading to bronchial relaxation and a decrease in the release of mediators of immediate hypersensitivity from mast cells. Delivery and Deposition The selection of a delivery system and the patients ability to use the device properly are critical factors in determining clinical success of inhaled corticosteroid therapy. Delivery systems can significantly affect both topical and systemic activity of ICS. 51,52 Metered dose inhalers (MDIs) are pressurized spray inhalers, available in suspension and solution, for which the user has to press down on the metal canister to release the medicine and then inhale. MDIs deliver approximately 15 to 35% of the administered dose to the lungs. Spacer chambers can be attached to MDIs to make them easier to use by people who find it hard to coordinate the press-andbreathe action. When using the spacer, the user can take several breaths to inhale the medicine, which is held in the chamber, so that it is more likely that the proper amount of medicine will reach the airways. MDIs with CFC propellants are no longer being actively marketed. Page 9

10 Dry-powder inhalers (DPIs) are breath-actuated devices that release the medicine in the form of a dry powder when the user breathes in. Although DPIs minimize the potential difficulties in coordinating the press-and-breathe action of the MDI, these delivery systems tend to result in more dosage variations than MDIs at low inspiratory flow rates (less than 20 L/min). Nebulizer therapy is not the recommended form of administration for most patients. 53 It is considered inferior to an MDI with spacer because of the inconvenience, decreased drug deposition, higher risk of side effects, and potentially higher cost. It may be considered an alternative in cases where patients lack the coordination to use the MDI with spacer, particularly in the very young and the very old. PHARMACOKINETICS 54,55,56,57,58,59,60,61,62,63 Several comparative studies have demonstrated that, when given in equipotent anti-inflammatory doses, fluticasone propionate (Flovent) and budesonide (Pulmicort) have less systemic effect, as measured by plasma cortisol, than the other agents. 64,65,66,67,68 There is, however, considerable intersubject variability in the rate of absorption of these agents from the lungs. 69 The NAEPP guidelines provide information regarding the relative potencies and dosages of each of the available agents, as seen in the table below. 70 It should be noted that these are not the FDA-approved doses, but rather those doses shown to be clinically effective and recommended by the NHLBI. Mometasone (Asmanex) for pediatrics and ciclesonide (Alvesco) were approved after the release of the 2007 NAEPP report and are therefore not contained in the following comparative chart. However, since 2008, mometasone and ciclesonide have been included in the GINA guidelines. Flunisolide (Aerospan) became commercially available in 2014 and is not addressed in the 2015 GINA guidelines. Page 10

11 NAEPP Expert Panel Report-3 Estimated Comparative Daily Dosages for Inhaled Corticosteroids (mcg/day) 71 Drug beclomethasone HFA inhalation aerosol (QVAR) budesonide inhalation powder (Pulmicort) budesonide inhaled suspension (Pulmicort Respules) fluticasone propionate HFA inhalation aerosol (Flovent HFA) mometasone inhalation powder (Asmanex Twisthaler) n/a= not available Adults and Children 12 Years of Age Lowdose Mediumdose Highdose Children (Five to 11 Years of Age) Lowdose Mediumdose Highdose > > > >600 1,200 >1, > >800 n/a n/a n/a 0.5 mg (ages 5 to 8 years) 1 mg (ages 5 to 8 years) 2 mg (ages 5 to 8 years) > > > >400 n/a n/a n/a Most of the agents in this class are recommended for twice use. The exceptions to this are mometasone (Asmanex DPI) and fluticasone furoate inhalation powder (Arnuity Ellipta), which can be dosed once GINA Guidelines for Equipotent Dosages of Inhaled Corticosteroids (mcg/day) 72 Drug beclomethasone HFA inhalation aerosol (QVAR) budesonide inhalation powder (Pulmicort) budesonide respules (Pulmicort Respules) ciclesonide inhalation aerosol (Alvesco) fluticasone propionate inhalation aerosol (Flovent) mometasone inhalation powder (Asmanex) Lowdose Adults Mediumdose High-dose Lowdose Children Mediumdose Highdose > >500 1, > > > >800 1, > >400 n/a n/a n/a >500 1,000 >1, > >320 1, > > > >500 1, > > Page 11

12 Onset of Action Drug Onset of action Maximum benefit Glucocorticoids beclomethasone HFA inhalation aerosol (QVAR) 73 one to two weeks three to four weeks budesonide inhalation powder (Pulmicort 24 hours one to two weeks Flexhaler) 74 budesonide suspension (Pulmicort Respules) 75 two to eight days four to six weeks ciclesonide inhalation aerosol (Alvesco) four weeks or longer flunisolide HFA inhalation aerosol (Aerospan) three to four weeks fluticasone furoate inhalation powder (Arnuity variable two weeks or longer Ellipta) 78 fluticasone propionate inhalation aerosol (Flovent 24 hours variable time to onset one to two weeks or longer HFA) 79 fluticasone propionate powder for inhalation 24 hours variable time to onset one to two weeks or longer (Flovent Diskus) 80 mometasone inhalation powder (Asmanex) 81 one to 2.5 hours one to two weeks or longer mometasone furoate inhalation aerosol (Asmanex variable one week or longer HFA) 82 budesonide/formoterol inhalation aerosol (Symbicort) 83 Glucocorticoids/Bronchodilator combinations 15 minutes for asthma, five minutes for COPD two weeks or longer fluticasone furoate/vilanterol (Breo Ellipta) minutes nr fluticasone propionate/salmeterol inhalation powder minutes one week or longer (Advair Diskus) 85 fluticasone propionate/salmeterol inhalation aerosol minutes one week or longer (Advair HFA) 86 mometasone/formoterol inhalation aerosol (Dulera) 87 variable one week or longer CONTRAINDICATIONS/WARNINGS 88,89,90,91,92,93,94,95,96,97,98 All of these agents are contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. A black box warning exists for all long-acting beta 2 agonists (LABAs; e.g., salmeterol and formoterol), as well as all combination products that contain them [e.g., fluticasone propionate/salmeterol (Advair HFA, Advair Diskus), budesonide/formoterol (Symbicort), mometasone/formoterol (Dulera), fluticasone furoate/vilanterol (Breo Ellipta)]. For Advair Diskus, Advair HFA, Symbicort, Dulera, and Breo Ellipta, the boxed warnings warn of the following: LABAs increase the risk of asthma-related deaths. Available data from controlled clinical trials suggest that LABAs increase the risk of asthmarelated hospitalization in pediatric and adolescent patients. These findings are considered a class effect of all LABAs. Page 12

13 When treating patients with asthma these agents should be prescribed for only those patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid (ICS), or whose disease severity clearly warrants initiation of treatment with both an ICS and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Advair, Symbicort, Dulera, or Breo Ellipta) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an ICS. Do not use these agents for patients whose asthma is adequately controlled on low or medium dose ICS. The inhalation powder formulations of fluticasone furoate (Arnuity Ellipta), fluticasone propionate (Flovent Diskus), fluticasone furoate/vilanterol (Breo Ellipta) and fluticasone propionate/salmeterol (Advair Diskus) are contraindicated in patients who have a severe hypersensitivity to milk proteins as these products contain milk proteins. Decreased bone mineral density (BMD) has been observed with the long-term administration of products containing inhaled glucocorticoids. 99 The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids, etc.), should be monitored and treated according to the current standards of care. There have been postmarketing reports of esophageal candidiasis for fluticasone propionate (Flovent Diskus, Flovent HFA). Risk Evaluation and Mitigation Strategy The products that contain a LABA (Advair Diskus, Advair HFA, Breo Ellipta, Dulera, and Symbicort) do not have REMS requirements by the FDA; however, a medication guide has been included in the product labeling. DRUG INTERACTIONS 100,101,102,103,104,105,106,107,108 The main route of metabolism for many corticosteroids is via the cytochrome P450 isoenzyme 3A4. Inhibitors of CYP3A4 (ritonavir, ketoconazole, itraconazole, clarithromycin, erythromycin) may increase the plasma concentration of inhaled corticosteroids (ICS). Fluticasone propionate (Flovent) use in combination with ritonavir has been associated with systemic corticosteroid effects, such as Cushing s syndrome and adrenal suppression. Products containing salmeterol, formoterol, or vilanterol (Advair Diskus, Advair HFA, Breo Ellipta, Dulera, Symbicort) should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within two weeks of discontinuation of such agents, because the action of the long-acting beta 2 agonist (LABA), on the cardiovascular system may be potentiated by these agents. Concomitant treatment with xanthine derivatives or diuretics may potentiate any hypokalemic effect of the LABA. Beta-blockers and diuretics should be used caution with drugs containing a LABA. Beta-blockers may interfere with the bronchodilatory effect of the LABA resulting in bronchospasm. Electrolyte abnormalities, such as hypokalemia, exacerbated by diuretics may be enhanced by concomitant beta-agonist usage. Page 13

14 ADVERSE EFFECTS Drug Cough Headache Nausea Glucocorticoids Oral candidiasis Pharyngitis Upper respiratory infection beclomethasone HFA inhalation aerosol (QVAR) budesonide inhalation powder (Pulmicort nr nr Flexhaler) 110 budesonide suspension >3 nr nr > (Pulmicort Respules) ciclesonide inhalation aerosol 112 < < 1 < (Alvesco) flunisolide HFA inhalation aerosol (Aerospan) nr nr nr fluticasone furoate inhalation powder (Arnuity Ellipta) reported < fluticasone propionate powder for inhalation < (Flovent Diskus) 115 fluticasone propionate inhalation aerosol reported (Flovent HFA) 116 mometasone inhalation 117 nr powder (Asmanex) mometasone furoate inhalation aerosol (Asmanex nr 3 5 reported reported 5 8 nr HFA) 118 Glucocorticoid/Bronchodilator Combinations budesonide/ formoterol inhalation aerosol reported reported (Symbicort) 119 fluticasone propionate/ salmeterol inhalation powder (Advair Diskus) 120 fluticasone propionate/salmeterol inhalation aerosol (Advair reported nr 16 HFA) 121 fluticasone furoate/vilanterol nr 5-7 nr (nr in asthma) (Breo Ellipta) 122 mometasone/ formoterol 123 nr nr nr inhalation aerosol (Dulera) Adverse effects are reported as a percentage. Adverse effects are obtained from package inserts and are not meant to be comparative or all inclusive. nr = not reported. Page 14

15 In 2010, the FDA issued new recommendations on the safe use of LABAs in the treatment of asthma, which also applied to the combination products of budesonide/formoterol (Symbicort), mometasone/formoterol (Dulera), and fluticasone propionate/salmeterol (Advair Diskus, Advair HFA). 124 The FDA recommends against the use of LABAs without the use of an asthma controller medication, such as an inhaled corticosteroid (ICS). Also, LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. They should be used long-term only in patients whose asthma is not adequately controlled on asthma controller medications. The REMS for LABAs includes a revised Medication Guide written specifically for patients, and a plan to educate healthcare professionals about the appropriate use of LABAs. In 2012, at the request of various manufacturers, the FDA released a number of products containing LABAs from their REMS requirements. These changes are outlined in the REMS section of this document. Additionally, in April 2011, to further evaluate the safety of LABAs when used in combination with ICS for the treatment of asthma, the FDA is requiring the manufacturers of LABAs to conduct five randomized, double-blind, controlled clinical trials to further evaluate the safety of LABAs when used in combination with ICS in comparison to ICS alone. These clinical trials began in 2011 and the FDA expects to receive results in SPECIAL POPULATIONS 126,127,128,129,130,131,132,133,134,135,136,137,138 Pediatrics Safety and effectiveness of budesonide/formoterol (Symbicort), ciclesonide (Alvesco), fluticasone furoate (Arnuity Ellipta), fluticasone propionate/salmeterol (Advair HFA), mometasone furoate (Asmanex HFA), and mometasone/formoterol (Dulera) in children under age 12 have not been proven. Safety and effectiveness of budesonide (Pulmicort Flexhaler) in children less than six years have not been established. Beclomethasone (QVAR) in children less than five years has not been proven safe or effective. Flunisolide (Aerospan) in children less than six years has not been proven safe or effective. Fluticasone propionate/salmeterol (Advair Diskus) and fluticasone propionate (Flovent HFA, Flovent Diskus) in children younger than four years have not been proven safe or effective. Mometasone (Asmanex) is approved for maintenance treatment of asthma as prophylactic therapy for children age four years and older. The safety and efficacy of fluticasone furoate/vilanterol (Breo Ellipta) has not been established in pediatric patients. Budesonide respules (Pulmicort Respules) are indicated specifically for children between 12 months and eight years of age. Pregnancy All products in this category are Pregnancy Category C except budesonide (Pulmicort), which is Pregnancy Category B. Page 15

16 Hepatic Impairment Close monitoring of patients using fluticasone propionate/salmeterol (Advair) or budesonide/formoterol (Symbicort) who have hepatic impairment is recommended due to accumulation of both active ingredients. Caution is advised when fluticasone furoate/vilanterol (Breo Ellipta) and fluticasone furoate (Arnuity Ellipta) are administered to patients with moderate to severe hepatic impairment. Formal studies of fluticasone propionate (Flovent Diskus, Flovent HFA) have not been performed in subjects with hepatic impairment; however, since it is predominantly metabolized by the liver, hepatitic impairment may lead to increased plasma concentrations; caution should be used in patients with hepatic impairment. Vilanterol is unaffected by hepatic impairment. Patients should be monitored for corticosteroid-related side effects. DOSAGES Drug beclomethasone HFA inhalation aerosol (QVAR) 139 budesonide inhalation powder (Pulmicort Flexhaler) 140 budesonide inhalation suspension (Pulmicort Respules) 141 Adult Doses Pediatric Doses Initial Maximum Initial Maximum mcg twice (previous bronchodilator use alone); mcg twice (previous inhaled corticosteroid therapy) 360 mcg twice 320 mcg twice 720 mcg twice Glucocorticoids Age 5 to 11 years: 40 mcg twice Age 6 to 17 years: 180 mcg twice Age 12 months to 8 years: Prior bronchodilator alone: 500 mcg once or 250 mcg twice Prior ICS: 500 mcg once or 250 to 500 mcg twice Prior oral glucocorticoid: 500 mcg twice or 1,000 mcg once Age 5 to 11 years: 80 mcg twice Age 6 to 17 years: 360 mcg twice Availability 40 mcg and 80 mcg MDI with HFA propellant (100 actuations per canister) Dose counter available for all strengths 90 mcg and 180 mcg DPI (60 and 120 actuations per canister, respectively) Dose counter available for all strengths , 500, 1,000 mcg per 2 ml respules via jet nebulizer Page 16

17 Dosages (continued) Drug ciclesonide inhalation aerosol (Alvesco) 142 flunisolide HFA inhalation aerosol (Aerospan) 143 fluticasone furoate inhalation powder (Arnuity Ellipta) 144 Adult Doses Pediatric Doses Initial Maximum Initial Maximum 80 mcg twice (patients who received bronchodilator alone) 80 mcg twice (patients who received inhaled corticosteroid) 320 mcg twice (patients who received oral corticosteroids) 160 mcg twice One Inhalation of 100 mcg or 200 mcg once (starting dose based on prior asthma therapy and disease severity) * Higher doses have not been studied. 160 mcg twice 320 mcg twice 320 mcg twice 320 mcg twice * Glucocorticoids Age 12 years and older: 80 mcg twice (patients who received bronchodilator alone) Age 12 years and older: 80 mcg twice (patients who received inhaled corticosteroid) Age 12 years and older: 120 mcg twice (patients who received oral corticosteroid) 80 mcg twice 200 mcg Age 12 years and older: one Inhalation of 100 mcg or 200 mcg once Age 12 years and older: 160 mcg twice Age 12 years and older: 320 mcg twice Age 12 years and older: 320 mcg twice 160 mcg twice * Age 12 years and older: 200 mcg Availability 80 mcg or 160 mcg MDI with HFA propellant (80 mcg is available as 60 actuations per canister) (160 mcg MDI is available as 60 actuations per canister) Dose counter available for all strengths 80 mcg or 160 mcg MDI with HFA propellant (5.1 g canister has 60 actuations per canister) (8.9 g canister has 120 actuations per canister) 100 or 200 mcg blister strip of inhalation only powder Page 17

18 Dosages (continued) Drug fluticasone propionate inhalation aerosol (Flovent HFA) 145 fluticasone propionate inhalation powder (Flovent Diskus) 146 mometasone furoate inhalation aerosol (Asmanex HFA) 147 Adult Doses Pediatric Doses Initial Maximum Initial Maximum 88 mcg twice (patients who received bronchodilator alone); mcg twice (patients who used ICS); 440 mcg twice (patients who used oral corticosteroids) 100 mcg twice (patients who received bronchodilators alone) mcg twice (patients who used ICS) 500 1,000 mcg twice (patients who used oral corticosteroids) Based on prior asthma therapy: two inhalations of 100 mcg or 200 mcg twice 440 mcg twice 440 mcg twice 880 mcg twice 500 mcg twice 500 mcg twice 1,000 mcg twice 400 mcg twice Glucocorticoids Age 4 to 11 years: 88 mcg twice Age 4 to 11 years: 50 mcg twice (when prior therapy is with bronchodilator alone or inhaled corticosteroid) Age 12 years and older: two inhalations of 100 mcg or 200 mcg twice Age 4 to 11 years: 88 mcg twice Age 4 to 11 years: 100 mcg twice Age 12 years and older: 400 mcg twice Availability 44, 110, 220 mcg MDI with HFA propellant (120 actuations per canister) Dose counter available for all strengths 50, 100, 250 mcg blister units (60 blisters per pack) Dose counter available for all strengths Pressurized meter dose inhaler available in two strengths: 100 mcg or 200 mcg per actuation Page 18

19 Dosages (continued) Drug mometasone inhalation powder (Asmanex Twisthaler) 148 budesonide/formoterol inhalation aerosol (Symbicort) 149 fluticasone furoate/vilanterol inhalation powder (Breo Ellipta) 150 The recommended starting dosages for asthma are based on prior asthma therapy (ICS) Adult Doses Pediatric Doses Initial Maximum Initial Maximum 220 mcg in evening (if on bronchodilator alone or inhaled corticosteroid) or 440 mcg twice (if on oral corticosteroid) Two inhalations twice of 80 mcg/ 4.5 mcg or 160 mcg/ 4.5 mcg Asthma: Low-to mid-dose ICS: One inhalation of 100 mcg/25 mcg once Mid- to high-dose ICS: One inhalation of 200 /25 mcg once COPD: One inhalation of 100 mcg/25 mcg once Glucocorticoids 440 mcg (single or divided doses) or 880 mcg Age 12 years and older: 220 mcg in evening (if on bronchodilator alone or inhaled steroid) or 440 mcg twice (if on oral corticosteroid) Age 4 to 11 years of age: 110 mcg once in the evening Age 12 years and older: 440 mcg (single or divided doses) or 880 mcg Age 4 to 11 years of age: 110 mcg once in the evening Glucocorticoid/Bronchodilator Combinations Two inhalations twice of 160 mcg/ 4.5 mcg Asthma: One inhalation of 200 mcg /25 mcg once COPD: One inhalation of 100 mcg/25 mcg once Age 12 years and older: two inhalations twice of 80 mcg/ 4.5 mcg or 160 mcg/ 4.5 mcg Age 12 years and older: two inhalations twice of 160 mcg/ 4.5 mcg Availability 110 or 220 mcg DPI (Available in 100 or 200 actuations per unit, respectively) Dose counter available for all strengths 80/4.5 and 160/4.5 mcg per actuation MDI with HFA propellant (120 actuations per canister) Dose counter available for all strengths 100/25 mcg per inhalation and 200/25 mcg per inhalation Dose counter available Page 19

20 Dosages (continued) Drug fluticasone propionate/salmeterol inhalation aerosol (Advair HFA) 151 fluticasone propionate/salmeterol inhalation powder (Advair Diskus) 152 mometasone/formoterol inhalation aerosol (Dulera) 153 The recommended starting dosages are based on prior asthma therapy Adult Doses Pediatric Doses Initial Maximum Initial Maximum Glucocorticoid/Bronchodilator Combinations Two inhalations of 45 mcg/ 21 mcg twice or 115 mcg/21 mcg twice or 230 mcg/ 21 mcg twice Asthma: 100 mcg/ 50 mcg twice to 500 mcg/ 50 mcg twice Maintenance treatment of COPD: 1 inhalation twice of 250 mcg/50 mcg For medium dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Two inhalations of 230 mcg/ 21 mcg twice Asthma: 500 mcg/ 50 mcg twice Dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Age 12 years and older: two inhalations of 45 mcg/ 21 mcg twice or 115 mcg/ 21 mcg twice or 230 mcg/ 21 mcg twice Age 4-11 years 100 mcg/ 50 mcg twice Age 12 years and older: one inhalation twice of 100/50, 250/50, or 500/50 mcg Age 12 years and older: For medium dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Age 12 years and older: two inhalations of 230 mcg/ 21 mcg twice -- Age 12 years and older: For medium dose ICS: two inhalations of 100 mcg/5 mcg twice For high dose ICS: two inhalations of 200 mcg/5 mcg twice Availability 45/21, 115/21, and 230/21 mcg per actuation MDI with HFA propellant (120 actuations per canister) Dose counter available for all strengths 100/50, 250/50, and 500/50 mcg per actuation Diskus DPI (60 blisters) Dose counter available for all strengths 100/5 and 200/5 mcg per actuation Dose counter available for all strengths CLINICAL TRIALS Search Strategy Studies were identified through searches performed on PubMed and review of information sent by manufacturers. Search strategy included the FDA-approved use of all drugs in this class. Randomized, controlled, comparative trials are considered the most relevant in this category. Studies included for Page 20

21 analysis in the review were published in English, performed with human participants, and randomly allocated participants to comparison groups. In addition, studies must contain clearly stated, predetermined outcome measure(s) of known or probable clinical importance, use data analysis techniques consistent with the study question, and include follow-up (endpoint assessment) of at least 80% of participants entering the investigation. Despite some inherent bias found in all studies, including those sponsored and/or funded by pharmaceutical manufacturers, the studies in this therapeutic class review were determined to have results or conclusions that do not suggest systematic error in their experimental study design. While the potential influence of manufacturer sponsorship and/or funding must be considered, the studies in this review have also been evaluated for validity and importance. Asthma beclomethasone MDI (QVAR) versus placebo The Treating Children to Prevent Exacerbations of Asthma (TREXA) study was a multi-center, 44-week, randomized, double-blind, placebo-controlled trial conducted in 288 children and adolescents with mild persistent asthma aged six to 18 years to evaluate the impact and severity of asthma exacerbations in patients who are receiving various combinations of medications for and rescue use. 154 Patients were randomly assigned to one of four treatment groups: twice beclomethasone with beclomethasone plus albuterol as rescue (combined group, n=71); twice beclomethasone with placebo plus albuterol as rescue ( beclomethasone group, n=72); twice placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group, n=71); and twice placebo with placebo plus albuterol as rescue (placebo group, n=74). Twice beclomethasone treatment was one puff of beclomethasone (40 mcg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 mcg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. Compared with the placebo group (49%; 95% confidence interval [CI], 37-61), the frequency of exacerbations was lower in the (28%; 95% CI, 18-40%; p=0.03), combined (31%; 95% CI, 21-43%; p=0.07), and rescue (35%; 95% CI, 24-47%; p=0.07) groups. Frequency of treatment failure was 23% (95% CI, 14-43%) in the placebo group, compared with 5.6% (95% CI, %) in the combined (p=0.012), 2.8% (95% CI, 0-10%) in the (p=0.009), and 8.5% (95% CI, 2-15%) in the rescue (p=0.024) groups. Compared with the placebo group, linear growth was 1.1 cm (SD 0.3) less in the combined and arms (p<0.0001), but not the rescue group (p=0.26). Only two individuals had severe adverse events; one in the beclomethasone group had viral meningitis and one in the combined group had bronchitis. The authors concluded that children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is inhaled corticosteroids (ICS). ICS as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of ICS treatment and related side-effects, such as growth impairment, can therefore be avoided. This study was funded by the National Heart, Lung and Blood Institute. Page 21

22 budesonide/formoterol MDI (Symbicort) versus budesonide DPI (Pulmicort) A double-blind, randomized, 12-week study conducted in 619 patients ages 12 and older with mild to moderate asthma to evaluate the efficacy and tolerability of once budesonide/formoterol versus once budesonide in patients stable with twice budesonide/formoterol. 155 After an initial four to five weeks of two inhalations twice budesonide/formoterol 80 mcg/4.5 mcg ( dose of 320 mcg/18 mcg), stable patients were randomized to one of four treatment groups. These groups included: two inhalations of twice of budesonide/formoterol 80 mcg/4.5 mcg ( dose 320 mcg/18 mcg); two inhalations once in the evening of budesonide/formoterol 160/4.5 mcg or 80/4.5 mcg ( dose of 320 mcg/9 mcg or 160/4.5 mcg); or two inhalations once of budesonide 160 mcg ( dose of 320 mcg). All budesonide/formoterol groups maintained significantly more favorable evening pre-dose forced expiratory volume in one second (FEV 1 ), morning peak expiratory flow (PEF), daytime/nighttime asthma symptoms, nighttime rescue medication use, and rescue medication-free days versus budesonide. Variables evaluated during the end of the once dosing interval included evening pre-dose FEV 1, evening PEF, daytime asthma symptoms, and daytime rescue medication use. They significantly favored twice budesonide/formoterol versus all treatments. Twice budesonide/formoterol demonstrated significantly more favorable results for symptomfree and asthma control days versus all treatments and awakening-free nights versus budesonide. Asthma Quality of Life Questionnaire and Asthma Control Questionnaire results significantly favored twice- budesonide/formoterol versus budesonide (p 0.018). All treatments were well tolerated. A double-blind, randomized, 12-week multicenter study was conducted in 521 patients ages six to 15 years with mild/moderate persistent asthma to assess the efficacy and tolerability of once budesonide/formoterol metered-dose inhaler (MDI) versus budesonide MDI (primary) and twice budesonide/formoterol MDI (secondary) in children/adolescents with asthma who have been stabilized with twice budesonide/formoterol MDI. 156 Patients had been stabilized during a four to five week run-in with two inhalations twice of budesonide/formoterol 40/4.5 mcg inhalations (160/18 mcg ). These patients were randomized to either continue on the stabilization regimen, to receive a reduced dose of two inhalations once every evening of budesonide/formoterol 80/4.5 mcg (160/9 mcg ), or two inhalations once every evening of budesonide 80 mcg (160 mcg ). The once or twice regimens of budesonide/formoterol were more effective than budesonide for evening PEF (primary variable) at the end of the 24 hour once dosing interval (p 0.027). Twice budesonide/formoterol demonstrated better efficacy versus once treatments for evening pre-dose FEV 1 (p 0.011), versus budesonide for daytime/nighttime rescue medication (p 0.023), and versus once budesonide/formoterol for daytime rescue medication (last 12 hours of once dosing) (p=0.032). There were no significant between-group differences for daytime/nighttime asthma symptoms, nighttime awakenings attributed to asthma, or health-related quality of life. Fewer patients experienced asthma worsening based on predefined criteria with twice budesonide/formoterol (8.2%) versus once budesonide (15.5%) (p=0.036) or once budesonide/formoterol (19.6%) (p=0.002). All treatments were well tolerated. budesonide/formoterol MDI (Symbicort) versus budesonide DPI (Pulmicort) versus formoterol MDI (Foradil) versus budesonide (Pulmicort) + formoterol (Foradil) versus placebo A 12-week, randomized, double-blind, double-dummy, placebo-controlled study was conducted to compare the efficacy and safety of budesonide/formoterol to each of its individual ingredients [budesonide, formoterol, or budesonide + formoterol] as well as to placebo. 157 Five hundred ninety-six Page 22

23 patients ages 12 years and older with moderate to severe persistent asthma and previously receiving an ICS were placed on budesonide 160 mcg twice. After two weeks, they were randomized to budesonide/formoterol 160/4.5 mcg twice ; budesonide 160 mcg twice + formoterol 4.5 mcg twice ; budesonide 160 mcg twice ; formoterol 4.5 mcg twice ; or placebo twice. The primary efficacy endpoints were mean change from baseline of FEV 1 and mean change from baseline in 12-hour FEV 1. The results were similar in the budesonide/formoterol and the budesonide + formoterol groups in all measures. The budesonide/formoterol group showed greater improvement in FEV 1 (p 0.049) than the individual budesonide, formoterol, and placebo. Also, fewer patients on budesonide/formoterol experienced worsening asthma symptoms (p 0.025). All of the treatments were well tolerated with similar safety profiles. A 12-week, randomized, double-blind, double-dummy, placebo-controlled, multicenter trial of 596 adult patients (ages 12 and older) with moderate to severe persistent asthma was conducted to evaluate patient reported outcomes (PROs) related to asthma therapy. 158 Patients received budesonide 160 mcg twice for the first two weeks. They were then randomized to receive two inhalations twice of one of five treatment arms: budesonide/formoterol 160/4.5 mcg; budesonide 160 mcg plus formoterol DPI 4.5 mcg; budesonide 160 mcg; formoterol DPI 4.5 mcg; or placebo. PROs were assessed in 553 patients 18 years or older using the standardized Asthma Quality of Life Questionnaire (AQLQ[S]), Medical Outcomes Survey (MOS) Sleep Scale, Patient Satisfaction with Asthma Medication (PSAM) questionnaire, diary data, and global assessments. Patients receiving budesonide/formoterol reported significantly greater improvements from baseline on the AQLQ(S) and asthma control variables (based on symptoms and rescue medication use; all p<0.001) versus placebo. Clinically important improvements (increase of 0.5 points) from baseline to end of treatment in AQLQ(S) overall scores were achieved by 43.6% of patients receiving budesonide/formoterol versus 22.6% of patients receiving placebo (p=0.001). The MOS Sleep Scale scores generally showed no differences among treatment groups. Patients receiving budesonide/formoterol had significantly greater PSAM questionnaire scores and better outcomes on physician-patient global assessments at end of treatment versus placebo (all p 0.001). budesonide/formoterol MDI (Symbicort) versus budesonide (Pulmicort) versus formoterol (Foradil) versus placebo A 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted in 480 patients age 12 years or older with mild to moderate persistent asthma treated with ICS for four weeks or more and with an FEV 1 of 60 to 90%. 159 After a two-week washout period, patients received either budesonide/formoterol 80/4.5 twice (n=123), budesonide 80 mcg twice (n=121), formoterol 4.5 mcg twice (n=114), or placebo (n=122). At the end of treatment, greater increases in FEV 1 occurred in the budesonide/formoterol group versus all of the other groups (0.37 versus 0.23, 0.17, and 0.03 L, respectively; p<0.005). Fewer patients receiving budesonide/formoterol withdrew due to worsening asthma versus the formoterol (42.1 and 18.4%) and placebo (56.6 versus 32.8%) groups. However, the results were similar, according to the authors, with respect to worsening asthma between the budesonide/formoterol and budesonide groups (21.5 versus 6.6%). The authors determined that in adults and adolescents with mild to moderate persistent asthma that twice budesonide/formoterol resulted in improved pulmonary function versus its component ingredients alone. All of the study drugs were well tolerated. Page 23

24 flunisolide MDI (Aerospan) versus placebo Two double-blind, parallel, placebo- and active-controlled studies evaluated patients with asthma. The primary endpoint was change from baseline in percent predicted FEV 1 after 12 weeks of treatment. 160 Patients (N=669) aged at least 12 years old who were previously treated with ICS were randomized to flunisolide (Aerospan) MDI (80 mcg, 160 mcg, or 320 mcg) twice, flunisolide chlorofluorocarbon (CFC) (250 mcg, 500 mcg, or 1,000 mcg) twice, or placebo. Compared to placebo, the primary endpoint was statistically significant for flunisolide MDI 160 mcg (p=0.012) and 320 mcg (p=0.003) doses, but not for the 80 mcg dose. 161 Patients four to 11 years of age (n=583) who were previously treated with bronchodilators alone or ICS were randomized to flunisolide MDI (80 mcg or 160 mcg) twice, flunisolide CFC (250 mcg or 500 mcg) twice, or placebo. Primary efficacy was only evaluated for patients six to 11 year old. Compared to placebo, the primary endpoint was statistically significant for flunisolide MDI 80 mcg (p=0.032) and 160 mcg doses (p=0.010). fluticasone propionate (Flovent) versus fluticasone propionate/salmeterol (Advair) A one-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and fluticasone propionate/salmeterol in achieving guideline-based measures of control: totally and well-controlled asthma. 162 Treatment was stepped-up until total control was achieved (or maximum 500 mcg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with fluticasone propionate/salmeterol than fluticasone propionate. Total control was achieved across all strata in 31% versus 19% of patients after dose escalation (p<0.001) and 41% versus 28% of patients at one year for fluticasone propionate/salmeterol and fluticasone propionate, respectively. Asthma became well controlled in 63% versus 50% after dose escalation (p<0.001) and in 71% versus 59% of patients at one year. Control was achieved more rapidly and at a lower corticosteroid dose with fluticasone propionate/salmeterol versus fluticasone propionate. Across all strata, 68% and 76% of the patients receiving fluticasone propionate/salmeterol and fluticasone propionate, respectively, were on the highest dose at the end of treatment. Exacerbation rates ( per patient per year) and improvement in health status were significantly better with fluticasone propionate /salmeterol. A multicenter, randomized, double-blind, four-week, parallel group trial of 248 pediatric patients (ages four to 17 years old) with persistent asthma was conducted to evaluate the effectiveness of fluticasone propionate/salmeterol 100 mcg/50 mcg compared to fluticasone propionate 100 mcg for the prevention of airflow limitation triggered by standardized exercise challenge. 163 Exercise challenge tests were performed during screening and approximately eight hours after administration of the blinded study medication on treatment day 28. After four weeks of therapy, both treatments provided protection following exercise challenge. The protection estimated by the maximal fall in FEV 1 was significantly better for fluticasone propionate/salmeterol (9.5 +/- 0.8%) compared with fluticasone propionate alone (12.7 +/- 1.1%, p=0.021). Statistically significant differences were not observed for asthma rescue-free days and asthma symptom-free days. A multicenter, randomized, parallel-group, double-blind study was performed comparing fluticasone/salmeterol 50/100 mcg twice a day and fluticasone propionate 200 mcg twice a day during a 26 week period to evaluate if the combination is non-inferior regarding symptom control and the effects on asthma control and lung function in children with symptomatic asthma. 164 For children with Page 24

25 symptomatic asthma despite low to moderate doses of ICS, evidence is still lacking whether to add a long-acting bronchodilator or to increase the dose of ICS. A total of 158 children age six to 16 years old, still symptomatic on fluticasone 100 mcg twice, were included in a four-week run-in period. The percentage of symptom-free days during the last 10 weeks of the treatment period did not differ between treatment groups (per protocol analysis: adjusted mean difference 2.6%; 95% CI, -8.1 to 13.4). Both groups showed substantial improvements of about 25 percentage points in symptom-free days (both p<0.001 from baseline). Lung function measurements (FEV 1, forced vital capacity [FVC], PEF rate, and maximal expiratory flow) did not differ between groups except for a slight advantage in maximal expiratory flow in the fluticasone propionate/salmeterol group at one week. No differences were found between fluticasone propionate and fluticasone propionate/salmeterol regarding exacerbation rates, adverse events, or growth. fluticasone propionate DPI (Flovent Diskus) versus salmeterol DPI (Serevent) versus fluticasone propionate/salmeterol DPI (Advair) A 12-week, randomized, double-blind study was conducted in patients 12 years and older (n=267) with persistent asthma who were symptomatic while taking as-needed, short-acting beta 2 -agonists (SABA) alone. 165 Treatments were administered twice via the fluticasone propionate/salmeterol diskus device: salmeterol 50 mcg; low-dose fluticasone propionate 100 mcg; or fluticasone propionate 100 mcg with salmeterol 50 mcg. At endpoint, fluticasone propionate/salmeterol were significantly (p 0.02) more effective than the individual agents used alone in improving morning and evening PEF rate and asthma symptoms. In addition, fluticasone and salmeterol effectively reduced rescue albuterol use (p 0.04). fluticasone propionate/salmeterol DPI (Advair) versus budesonide/formoterol MDI (Symbicort) A multicenter, parallel group, double-blind, double-dummy, randomized 24-week study was designed to compare the efficacy of salmeterol/fluticasone propionate combination 50/250 mcg one inhalation twice with formoterol/budesonide combination 6/200 mcg two inhalations twice in patients (n=1,391) with persistent asthma, currently receiving 1,000-2,000 mcg/day of ICS. 166 The primary endpoint, mean rate of all exacerbations over 24 weeks, was similar in both treatment groups (p=0.571). A reduction in the rate of exacerbations over time was observed in both treatment groups. Overall, there was a 30% lower annual rate of moderate/severe exacerbations in the salmeterol/fluticasone propionate group compared with the formoterol/budesonide group (95% CI, 0-49%; 52% reduction versus 1% increase; p=0.059). Similar improvements in lung function, asthma symptoms, and rescue medication usage were seen with both treatments and both were well tolerated. mometasone furoate DPI (Asmanex Twisthaler) versus placebo A 12-week, multicenter, double-blind, parallel-group, placebo-controlled study evaluating two dosing regimens of mometasone (100 mcg every evening and 100 mcg twice ) in 296 children ages four to 11 years of age with asthma and prior use of ICS. 167 The primary efficacy variable was the change in FEV 1 from baseline to endpoint. The average change in FEV 1 for the group receiving a dose was 4.73 points while the group receiving a twice dose was 5.52 points (p 0.002). The active treatments did not differ from placebo in adverse event reporting. Page 25

26 mometasone furoate DPI (Asmanex Twisthaler) versus budesonide DPI (Pulmicort) versus placebo An eight-week, multicenter, placebo-controlled, double-blind, double-dummy study was conducted in 262 patients (12 years of age or older) with moderate persistent asthma to compare the safety and efficacy of once mometasone DPI to budesonide DPI and placebo. 168 Patients were randomized to once morning treatment with mometasone 440 mcg, low-dose budesonide 400 mcg, or placebo. The primary efficacy endpoint was percent change in FEV 1 from baseline to the final evaluable visit. At endpoint, the FEV 1 was significantly greater (p<0.01) in the mometasone group (8.9%) than both the budesonide group (2.1%) and placebo group (-3.9%). Secondary efficacy variables including morning and evening PEF rates, albuterol use, percentage of asthma symptom-free days, and physicianevaluated response to therapy were also significantly improved at endpoint in the mometasone group compared with both the placebo and budesonide groups (p<0.05). Both active treatments were well tolerated. mometasone/formoterol MDI (Dulera) versus mometasone (Asmanex HFA) versus formoterol (Foradil) versus placebo A 26-week, placebo-controlled trial evaluated 781 patients 12 years of age and older with persistent asthma that were not well controlled on medium doses of ICS. 169 The study compared mometasone/formoterol MDI 100 mcg/5 mcg, mometasone furoate MDI 100 mcg, formoterol fumarate MDI 5 mcg and placebo; each administered as two inhalations twice. All other maintenance therapies were discontinued. The FEV 1AUC (0-12hr) was assessed as a co-primary efficacy endpoint to evaluate the contribution of the formoterol component. Patients receiving the combination mometasone/formoterol had significantly higher increases from baseline at week 12 in mean FEV 1AUC (0-12 hr) compared to mometasone furoate and placebo (both p<0.001). These differences were maintained through week 26. Clinical deterioration in asthma or reductions in lung function was another primary endpoint to evaluate the contribution of mometasone furoate. Deteriorations in asthma were defined as any of the following: a 20% decrease in FEV 1 ; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol. Fewer patients who received the combination mometasone/formoterol (30%) reported an event compared to patients who received formoterol (54%) (p<0.001). mometasone/formoterol MDI (Dulera) versus mometasone (Asmanex HFA) versus formoterol (Foradil) versus placebo A 12-week double-blind trial evaluated 728 patients ages 12 years and older with persistent asthma that were uncontrolled on high dose ICS. 170 This study compared mometasone/formoterol 200 mcg/5 mcg with mometasone/formoterol 100 mcg/5 mcg and mometasone furoate 200 mcg, each administered as two inhalations twice by MDIs. All other maintenance therapies were discontinued. Patients receiving either mometasone/formoterol dosages had significantly greater increases from baseline at day one in mean FEV 1AUC (0-12 hr) compared to mometasone furoate. The difference was maintained over 12 weeks of therapy. Mean change in trough FEV 1 from baseline to week 12 was also assessed to evaluate the relative contribution of mometasone furoate to the combination product. A greater numerical increase in the mean trough FEV 1 was observed for the higher strength mometasone/formoterol compared to the lower strength mometasone/formoterol and mometasone monotherapy. Clinical deterioration in asthma or reduction in lung function was Page 26

27 assessed as an additional endpoint. Fewer patients who received either strength mometasone/formoterol (12% for each group) compared to mometasone furoate (18%) alone reported an event. ciclesonide MDI (Alvesco) versus budesonide DPI (Pulmicort) A 12-week, multicenter, randomized study to compare the efficacy of ciclesonide to budesonide enrolled 544 patients ages 12 to 75 years. 171 Patients were randomized to receive inhaled ciclesonide 80 or 320 mcg or budesonide 200 mcg twice for 12 weeks. The study was designed in a double-blind manner with respect to the ciclesonide dose and open-label for budesonide because a placebo for budesonide was not available. Efficacy and tolerability assessments were performed at baseline and weeks four, eight, and 12. The primary endpoint was the change from baseline in FEV 1 at 12 weeks. Secondary endpoints included changes from baseline in morning PEF, asthma symptom scores, and rescue medication use. The results of this study in patients with primarily mild to moderate asthma suggest that patients using either dose of ciclesonide (80 or 320 mcg ) had similar improvements in pulmonary function, control of asthma symptoms, and reduced need for rescue medications as those patients who received budesonide 200 mcg twice. ciclesonide MDI (Alvesco) versus fluticasone (Flovent) A 12-week, double-blind, parallel-group study compared the efficacy and safety of once ciclesonide and twice fluticasone in patients ages 12 to 75 years with persistent asthma. 172 Patients were randomized to once ciclesonide 80 mcg (n=278), ciclesonide 160 mcg (n=271), or twice fluticasone 88 mcg (n=259). Significant improvements from baseline were seen in all three treatment groups for FEV 1, asthma symptom scores, and rescue medication use (all p<0.0001). Asthma exacerbation rates were low. Adverse event reporting indicated good tolerability of all treatments. fluticasone furoate (Arnuity Ellipta) versus fluticasone propionate (Flovent Diskus) This randomized, double-blind, double-dummy, placebo-controlled, multicenter study, enrolled 343 patients with asthma, aged 12 years or older who were not controlled by their current ICS therapy. 173 The primary endpoint was change from baseline in pre-dose evening FEV 1 at the end of the 24-week treatment period. Patients randomly received fluticasone furoate (100 mcg) once, placebo once, or twice administered fluticasone propionate (250 mcg). At week 24, once fluticasone furoate and twice fluticasone propionate significantly improved pre-dose evening FEV 1 (+146 ml; p=0.009) compared with placebo (+145 ml; p=0.011). The secondary endpoint of percentage rescuefree 24-hour periods, was increased with fluticasone furoate (+14.8%; p<0.001) and fluticasone propionate (+17.9%; p<0.001) compared to placebo. fluticasone furoate/vilanterol (Breo Ellipta) versus fluticasone furoate (Arnuity Ellipta) In two 12-week randomized, double-blind, parallel-group trials, the efficacy of fluticasone furoate/vilanterol on lung function in subjects with asthma not controlled on their current treatments of ICS or ICS/LABA. 174 In both studies, all inhalations were administered once. In study 1, 609 patients were randomized to fluticasone furoate/vilanterol 100/25 mcg, fluticasone furoate 100 mcg, or placebo. Weighted mean FEV 1 (0 to 24 hours) was assessed in a subset of subjects (n=309). At week 12, change from baseline in weighted mean FEV 1 was significantly greater for fluticasone furoate/vilanterol 100/25 mcg compared with placebo (302 ml; 95% CI, ; p<0.001); change from baseline in weighted mean FEV 1 for fluticasone furoate/vilanterol 100/25 was numerically greater Page 27

28 than fluticasone furoate 100 mcg, but not statistically significant (116 ml; 95% CI, ). At week 12, change from baseline in trough FEV 1 was significantly greater for fluticasone furoate/vilanterol 100/25 compared with placebo (172 ml; 95% CI, ; p<0.001); change from baseline in trough FEV 1 for fluticasone furoate/vilanterol 100/25 mcg was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (36 ml; 95% CI, ). In study 2, 1,039 patients were randomized to fluticasone furoate/vilanterol 100/25 mcg, fluticasone furoate/vilanterol 200/25 mcg, or fluticasone furoate 100 mcg. 175 The change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol 100/25 mcg compared with fluticasone furoate 100 mcg (108 ml; 95% CI, ; p<0.001) at week 12. fluticasone furoate/vilanterol (Breo Ellipta) versus fluticasone propionate (Flovent Diskus) In a 24-week randomized, double-blind, parallel-group trial, patients (n=586) not controlled on their current treatments of ICS or combination therapy consisting of an ICS plus a LABA were randomized to fluticasone furoate/vilanterol 200/25 mcg, fluticasone furoate 200 mcg, or fluticasone propionate 500 mcg. 176 All inhalations were administered once, with the exception of fluticasone propionate, which was administered twice. The change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol 200/25 mcg compared with fluticasone furoate 200 mcg (136 ml; 95% CI, 1-270; p=0.048) at week 24. The change from baseline in trough FEV 1 was significantly greater for fluticasone furoate/vilanterol 200/25 mcg compared with fluticasone furoate 200 mcg (193 ml; 95% CI, ; p<0.001) at week 24. Patients receiving fluticasone furoate/vilanterol 200/25 mcg had significantly greater improvements from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with patients receiving fluticasone furoate 200 mcg. fluticasone furoate/vilanterol (Breo Ellipta) versus fluticasone propionate/salmeterol (Advair) In a randomized, double-blind, double-dummy, parallel group study, 403 patients received fluticasone furoate/vilanterol 100/25 mcg once in the evening, and 403 patients received fluticasone propionate/salmeterol 250/50 mcg twice. 177 Improvements from baseline in weighted mean FEV 1 (0 to 24 hours) were observed with both fluticasone furoate/vilanterol (341 ml) and fluticasone propionate/salmeterol (377 ml); the adjusted mean treatment difference was not statistically significant ( 37 ml; 95% CI, 88 to 15, p=0.162). There were no differences between 0 to 4 hour serial weighted mean FEV 1, trough FEV 1, asthma control and quality-of-life questionnaire scores, and reported exacerbations between treatments. COPD budesonide/formoterol (Symbicort) versus budesonide (Pulmicort) versus formoterol (Foradil) versus placebo In a 12-month, randomized, double-blind, placebo-controlled, parallel-group study in 812 adults (mean age 64 years, mean FEV 1 36%), patients with moderate to severe COPD received two inhalations twice of either budesonide/formoterol 160/4.5 mcg, budesonide 200 mcg, formoterol 4.5 mcg, or placebo. 178 Severe exacerbations and FEV 1 were the primary variables. Other variables including PEF, COPD symptoms, health-related quality of life (HRQL), mild exacerbations, use of reliever beta 2 - agonist, and safety variables were recorded. Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24% versus placebo and 23% versus formoterol. For Page 28

29 patients receiving budesonide/formoterol, FEV 1 increased by 15% versus placebo and 9% versus budesonide. Morning PEF improved significantly on day one versus placebo and budesonide. After one week, morning PEF was improved versus placebo, budesonide, and formoterol. Improvements in morning and evening PEF versus comparators were maintained over 12 months. Budesonide/formoterol decreased all symptom scores and use of reliever beta 2 -agonists significantly versus placebo and budesonide, and improved HRQL versus placebo. All treatments were well tolerated. The SHINE trial was a six-month, double-blind, multicenter trial that evaluated the efficacy and tolerability of budesonide/formoterol in 1,704 patients ages 40 years and older with moderate to very severe COPD. 179 Patients were randomized to receive twice treatment with two inhalations of budesonide/formoterol 160/4.5 mcg or 80/4.5 mcg, budesonide 160 mcg + formoterol 4.5 mcg, budesonide 160 mcg, formoterol 4.5 mcg, or placebo. Primary outcomes measures included pre-dose and one-hour post-dose FEV 1 over the six month treatment period. Budesonide/formoterol 160/4.5 mcg twice a day (320/9 mcg) improved both pre-dose and one-hour post-dose FEV 1 compared to either of the components alone or placebo (p for all). At the lower dose of 80/4.5 mcg twice a day (160/9 mcg), there was significantly greater improvement in pre-dose FEV 1 and one-hour post-dose FEV 1 compared with budesonide and placebo (p for all), but not compared to formoterol. Budesonide/formoterol had a safety profile comparable with that of the mono components and placebo. budesonide/formoterol (Symbicort) versus fluticasone propionate/salmeterol (Advair) versus salbutamol versus placebo In a double-blind, double-dummy, crossover study, 90 patients (age 40 years and older; FEV 1 30 to 70%) were randomized to a single dose (two inhalations) of budesonide/formoterol 160/4.5 mcg, fluticasone propionate/salmeterol 250/25 mcg, salbutamol 100 mcg, or placebo on four visits. 180 Outside the United States albuterol is known as salbutamol. The primary endpoint was change in FEV 1 five minutes after drug inhalation; secondary endpoints included inspiratory capacity (IC) and perception of onset of effect. Budesonide/formoterol significantly improved FEV 1 at five minutes compared with placebo (p<0.0001) and fluticasone propionate/salmeterol (p=0.0001). Significant differences were first observed at three minutes. Onset of effect was similar with budesonide/formoterol and salbutamol. Improvements in FEV 1 following active treatments were superior to placebo after 180 minutes (all p<0.0001); both combinations were better than salbutamol at maintaining FEV 1 improvements (p ) at 180 minutes. Active treatments improved IC at 15 and 185 minutes compared with placebo (p<0.0001). Maximal IC was greater with budesonide/formoterol than fluticasone propionate/salmeterol (p=0.0184) at 65 minutes. Patients reported a positive response to the perceptions of the onset of effect question shortly after receiving active treatments (median time to onset was five minutes for active treatments versus 20 minutes for placebo), with no significant difference between active treatments. Budesonide/formoterol has an onset of bronchodilatory effect in patients with COPD and reversible airway obstruction that is faster than fluticasone propionate/salmeterol and similar to salbutamol. Page 29

30 fluticasone propionate DPI (Flovent) versus salmeterol DPI (Serevent) versus fluticasone propionate/salmeterol DPI (Advair) In a double-blind, parallel-group, placebo-controlled study, 1,465 patients with COPD were randomized to receive salmeterol 50 mcg twice, high-dose fluticasone 500 mcg twice, fluticasone propionate/salmeterol 500/50 mcg twice, or placebo. 181 After 12 months, all active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV 1 significantly more than did placebo (treatment difference 133 ml; 95% CI, 105 to 161; p<0.0001), salmeterol (73 ml; 95% CI, 46 to 101; p<0.0001), or fluticasone alone (95 ml; 95% CI, 67 to 122; p<0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration. fluticasone furoate/vilanterol (Breo Ellipta) versus placebo Two similarly designed double-blind, randomized, placebo-controlled trials (n=2,254) assessed the efficacy of fluticasone furoate/vilanterol on lung function in patients with stable moderate-to-severe COPD. 182,183 Study 1 randomized 1,224 patients to fluticasone furoate/vilanterol 100 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo once. Study 2 randomized 1,030 patients to fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 100 mcg/25 mcg, fluticasone furoate 100 mcg, or vilanterol 25 mcg or placebo once. Co-primary endpoints were the zero to four hour weighted mean FEV 1 on day 168 and change from baseline in trough (23-24 hour post-dose) FEV 1 on day 169. Because of the large number of comparisons in these trials, a pre-defined statistical testing hierarchy design was employed, placing the highest dosage of fluticasone/vilanterol on level 1 of the hierarchy. Significance was required for all comparisons in level 1 to allow statistical significance to be inferred for differences in endpoints further down the hierarchy. In Study 1, the increase in zero to four hour weighted mean FEV 1 on day 168 and the adjusted mean trough FEV 1 on day 169 for the comparison of fluticasone furoate/vilanterol 200 mcg/25 mcg versus placebo were significant. The difference between this combination and vilanterol 25 mcg alone in adjusted mean trough FEV 1 was not significant and thus no inference can be drawn for comparisons of the 100 mcg/25 mcg strength with placebo or its components. Differences in the co-primary endpoints between the combination and placebo in the 100 mcg/25 mcg strength analysis were similar to those observed with the 200 mcg/25 mcg strength. In Study 2, treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg resulted in a significantly improved adjusted zero to four hour weighted mean FEV 1 at day 168 compared to placebo (173 ml; 95% CI, ; p<0.001). The co-primary adjusted mean trough FEV 1 at day 169 by 115 ml was also significant versus placebo (95% CI, ; p<0.001). In two randomized, double-blind, parallel-group, multinational, one-year trials, a total of 3,255 COPD patients with a history of exacerbations received once treatment with vilanterol alone or combined with various doses of fluticasone furoate. 184 Results from these studies are presented individually and in a pooled analysis. Patients 40 years of age, with COPD and a history of smoking of 10 or more pack-years, a ratio FEV 1 to FVC of 0.70 after bronchodilators (and an FEV 1 of 70% of predicted) and a documented history of at least one exacerbation in the previous year were eligible. Study 1 enrolled 1,622 patients; study 2 enrolled 1,633 patients. After a four-week run-in period of treatment with open-label fluticasone propionate (250 mcg)/salmeterol (50 mcg) twice to Page 30

31 establish a stable baseline and adherence, patients were randomized 1:1:1:1 to 25 mcg vilanterol alone or 25 mcg vilanterol combined with either 50 mcg, 100 mcg, or 200 mcg fluticasone furoate once in the morning. The primary outcome measure was the yearly rate of moderate and severe exacerbations. Moderate exacerbation was defined as worsening symptoms for two days requiring treatment with oral corticosteroids, antibiotics or both. Severe exacerbations were similar but patients required hospitalization. In Study 1, the difference in yearly rate of exacerbations between the fluticasone furoate/vilanterol 200/25 mcg group and the vilanterol alone group did not reach significance (least squares mean yearly rate 0.9 fluticasone/vilanterol versus 1.05 vilanterol; p=0.1093). The study design employed a statistical hierarchical testing procedure so comparisons of other dosage groups could not be used to infer significance. In Study 2, the differences in yearly rate of exacerbations between all fluticasone furoate/vilanterol groups and the vilanterol alone group were significant. In the 100 mcg fluticasone furoate/25 mcg vilanterol group (approved dose), the least squares mean yearly rate was 0.9 compared to 1.14 in the vilanterol alone group (p=0.0244). In the pooled analysis, the difference between all doses of fluticasone furoate/vilanterol and vilanterol alone was significant and the combination of fluticasone 100 mcg and vilanterol 25 mcg significantly reduced the yearly rate of moderate and severe exacerbations compared to vilanterol alone (0.81 versus 1.11). In these trials, the difference in exacerbation rate was driven primarily in a reduction in moderate exacerbations; few severe exacerbations occurred and the difference between groups in severe exacerbation rate was not significant. The incidence of fractures and pneumonia was higher with fluticasone furoate/vilanterol than with vilanterol alone. Fractures were reported in 19 (100 mcg fluticasone furoate/25 mcg vilanterol) patients compared to eight vilanterol patients. Overall, pneumonia occurred at about twice the rate in the fluticasone furoate/vilanterol groups compared to the vilanterol group (100 mcg fluticasone furoate/25 mcg vilanterol: 51 events versus 25 mcg vilanterol: 27 events). One case of pneumonia in the group receiving fluticasone furoate/vilanterol 100/25 mcg and seven cases of pneumonia in the group receiving fluticasone furoate/vilanterol 200/25 mcg were fatal compared to none in the vilanterol or fluticasone furoate monotherapy groups. fluticasone furoate/vilanterol (Breo Ellipta) versus fluticasone propionate/salmeterol (Advair Diskus) Three randomized, double-blind, double-dummy, parallel-group, comparative multicenter studies compared the efficacy and safety of fluticasone furoate/vilanterol 100/25 mcg once, or fluticasone propionate/salmeterol 250/50 mcg twice for 12 weeks in 1,858 patients with moderate to very severe COPD. 185 The primary endpoint of each study was change from baseline trough in 0 24 hour weighted mean FEV 1 (wmfev 1 ) on day 84, using intent-to-treat population. Improvements in 0 24 hour wmfev 1 were seen with both fluticasone furoate/vilanterol 100/25 mcg and fluticasone propionate/salmeterol 250/50 mcg compared with baseline trough in all three studies and in the pooled analysis. In study 1, the treatment difference between fluticasone furoate/vilanterol and fluticasone propionate/salmeterol was statistically significant (80 ml p<0.001); however, in studies 2 and 3, the difference was not statistically or clinically significant (29 ml, p=0.267; 25 ml, p=0.137, respectively). In the pooled analysis of all three studies, there was a small statistically significant but clinically insignificant treatment difference of 41 ml (p<0.001); this is below the suggested minimal clinically important difference for lung function. Both treatments were well tolerated with generally similar safety profiles. Page 31

32 Clinical Trials: Safety There is concern that prolonged treatment with high doses of ICS may have a detrimental effect on bone mineral density (BMD), cause ocular toxicity, suppress the adrenal/pituitary axis, and inhibit vertical growth. budesonide (Pulmicort Respules) versus reference treatments Pooled safety data from budesonide inhalation suspension studies (n=2,356) found there were small differences in short-term growth velocity between children who received budesonide inhalation suspension and those who received reference treatment in two of five trials that evaluated this variable. 186 No posterior subcapsular cataracts were reported in any study. The frequencies of oropharyngeal events and infection with budesonide inhalation suspension were comparable with those of reference treatments. No increased risk of varicella or upper respiratory tract infection was apparent, and budesonide inhalation suspension did not cause significant adrenal suppression in studies assessing this variable. Data from the inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study evaluated the safety of once budesonide use over three years in patients aged five to 66 years with mild, persistent asthma (n=7,221). 187 The most commonly reported events included respiratory infections, rhinitis, pharyngitis, bronchitis, viral infections, and sinusitis. Fewer asthma-related, serious adverse events were reported with budesonide (2.2%) compared with placebo (3.8%). Oral candidiasis was reported more frequently with budesonide (1.2%) than with placebo (0.5%). A further analysis of the START trial was conducted to determine whether severe asthma exacerbations are associated with a persistent decline in lung function. 188 This study was a three-year, randomized, double-blind trial that enrolled 7,165 patients (five to 66 years of age) with persistent asthma. There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV 1 percent predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (p<0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV 1 percent predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (p=0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (p=0.042). Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of ICS is associated with an attenuation of the decline. fluticasone propionate (Flovent) versus placebo A randomized, double-blind, placebo-controlled study of 160 patients with asthma who had minimal previous exposure to corticosteroids was performed to evaluate the effects of treatment with fluticasone versus placebo on bone, hypothalamic-pituitary-adrenal (HPA) axis function, and the eyes in patients with asthma. 189 Patients received low-dose fluticasone at 88 mcg twice, high-dose fluticasone at 440 mcg twice, or placebo twice for two years. Long-term treatment with 88 mcg of fluticasone twice was comparable to placebo in all skeletal, ophthalmic, and HPA axis function assessments. Treatment with fluticasone at 440 mcg twice resulted in no significant Page 32

33 effects on bone mineral density and a statistically significant, but not clinically important, temporary reduction in cortisol production. fluticasone propionate MDI (Flovent) versus budesonide MDI (Pulmicort) Forty children (age one to three years) with mild asthma were studied in a three-way crossover, randomized, placebo-controlled, double-blind trial. 190 Treatment with medium-dose fluticasone MDI 200 mcg twice was compared with low-dose budesonide MDI 200 mcg twice and placebo, all given via a spacer device. Systemic steroid activity was assessed after one and four weeks of treatment by measured increase in lower-leg length. The increases in lower-leg length during placebo, budesonide, and fluticasone treatments were 85, 45, and 34 mcm/day, respectively. Compared to placebo, the growth in lower-leg length was significantly reduced from both corticosteroid treatments. The differences between budesonide and placebo (40 mcm/day) and between fluticasone and placebo (51 mcm/day) were statistically significant. The difference between the two active treatment groups, fluticasone and budesonide, was not statistically significant. fluticasone propionate/salmeterol DPI (Advair) and fluticasone propionate DPI (Flovent) A randomized, multicenter, double-blind, active-controlled, parallel-group study in 203 children with persistent asthma who were symptomatic during ICS therapy were examined to compare the safety of twice treatment of inhaled fluticasone/salmeterol with that of fluticasone alone. 191 The subjects received either fluticasone/salmeterol (100/50 mcg) or low-dose fluticasone (100 mcg) alone twice for 12 weeks. The results of the study showed that the safety profile of fluticasone/salmeterol was comparable to that of fluticasone alone with the overall incidence of adverse events being 59% for fluticasone/salmeterol and 57% for fluticasone. The changes in heart rate, blood pressure, and laboratory variables were infrequent and similar between both groups, and no patients had clinically significant abnormal electrocardiographic findings during treatment. The incidence of withdrawals within the study due to asthma exacerbations was 2% in the fluticasone/salmeterol group and 5% in the fluticasone group. Therefore, the study concluded that in children with persistent asthma, fluticasone/salmeterol twice was well tolerated, with a safety profile similar to that of fluticasone used alone. budesonide DPI (Pulmicort) versus fluticasone propionate DPI (Flovent) The systemic effects of high-dose budesonide 1,600 mcg/day and high-dose fluticasone 1,500 mcg/day were compared in a randomized, double-blind, cross-over study of 60 adult patients with moderate to severe asthma not controlled on high-dose beclomethasone or budesonide. 192 HPA axis suppression of the two treatment groups was assessed by morning serum cortisol and 12-hour nocturnal urinary cortisol excretion measured at the end of each treatment period. Neither treatment produced significant suppression of either parameter compared to baselines. The ratio between the AUC serum cortisol measured after fluticasone treatment and after budesonide treatment was 0.99, indicating equivalent effects on the HPA axis. Two exacerbations of acute asthma occurred during budesonide treatment, and none occurred during fluticasone treatment. Both treatments were well tolerated. Bone Mineral Density and Fracture Several studies have been performed to evaluate the relative effects of the various agents on bone mass and metabolism. Page 33

34 A multicenter, double-blind, parallel-group study randomized 69 adults with mild to moderate asthma to treatment with medium or high doses of fluticasone propionate or beclomethasone. 193 After one year, there was no loss of trabecular or integral bone in the distal radius or tibia in any of the patients. However, a meta-analysis of included randomized controlled trials (16 trials; n=17,513) of budesonide or fluticasone propionate compared to control treatment for COPD greater than 24 weeks duration and controlled observational studies (seven studies; n=69,000) of ICS associated fracture risk. 194 This study reported a modest but statistically significant increase in risk of fracture with long-term use of fluticasone propionate and budesonide. Linear Growth Orally ICS may cause a reduction in growth velocity when administered to children and adolescents. 195 A reduction of growth velocity in children and adolescents may occur as a result of poorly controlled asthma or from use of corticosteroids. Evidence on growth velocity and height over an extended time period is available from the Childhood Asthma Management Program (CAMP) trial that compared budesonide with nedocromil and placebo in 1,041 children followed for four to six years. 196 A difference consistent with the above magnitude occurred during the first year of the study. However, in long-term follow up, the difference in growth velocity was not maintained, and all groups had similar growth velocity at the end of treatment. There was still a one centimeter difference between the study groups at the end of treatment. A slight difference in bone age suggests the potential for catch-up for the ICS group. A follow-on study with 943 of the original 1,041 children showed a statistically significant reduction of 1.2 cm in mean adult height (95% CI, -1.9 to -0.5) for the budesonide arm as compared to the placebo group (p=0.001). 197 This magnitude height difference is consistent with the results seen after two years of treatment (-1.3 cm; 95% CI, -1.7 cm to -0.9 cm). 198 An ancillary study of the CAMP trial demonstrated that low-dose budesonide 400 mcg/day over a three-year period had no effects on HPA axis function in children with mild to moderate asthma. 199 Growth in children taking corticosteroids by any route should be carefully monitored. META-ANALYSES In 2007, a meta-analysis of randomized trials in children and adults was completed comparing fluticasone to either beclomethasone or budesonide in the treatment of chronic asthma. 200 Two reviewers independently assessed articles for inclusion and methodological quality. Seventy-one studies (14,602 participants) representing 74 randomized comparisons met the inclusion criteria. When compared at a fluticasone-to-budesonide or beclomethasone dose ratio of 1:2, fluticasone produced a significantly greater end of treatment forced expiratory volume in 1 second (FEV 1 ;0.04 L; 95% confidence interval [CI], 0 to 0.07 L), and end of treatment and change in morning peak expiratory flow (PEF). However, there was no significant change in FEV 1 or evening PEF. This applied to all drug doses, age groups, and delivery devices. No difference between fluticasone and beclomethasone or budesonide was seen for trial withdrawals. Fluticasone led to fewer symptoms and less rescue medication use. There was a greater likelihood of pharyngitis with fluticasone when compared to budesonide or beclomethasone with no difference in the likelihood of oral candidiasis. When comparing the doses of these agents in a dose ratio of 1:1, fluticasone produced a statistically significant difference in morning PEF, evening PEF, and FEV 1 over both budesonide and Page 34

35 beclomethasone. The effects on exacerbations were mixed. There were no significant differences in the incidence of hoarseness, pharyngitis, candidiasis, or cough at the equivalent dose ratio. A meta-analysis of published and unpublished literature evaluated the impact of long-term inhaled corticosteroid use on bone density in adult patients with asthma or COPD. 201 The authors found that long-term use was not associated with significant changes in bone density. Data from the United Kingdom based General Practice Research Database have been evaluated to determine whether children or adolescents exposed to inhaled corticosteroids (ICS) are at a higher risk of having bone fractures compared with non-exposed individuals. 202 The authors concluded that they were not. In 2010, a meta-analysis of randomized, controlled trials (RCTs) that compared the strategy of increasing the dose of ICS to continuing the same ICS dose in the home management of asthma exacerbations in children or adults with persistent asthma who receive maintenance ICS. 203 Five RCTs (four parallel-group and one cross-over) involving a total of 1,250 patients (28 children and 1,222 adults) with mild to moderate asthma were included. The mean baseline ICS dose was 555 mcg (range 200 mcg to 795 mcg) and the mean ICS dose achieved following the increase was 1,520 mcg (range 1,000 mcg to 2,075 mcg), in beclomethasone dipropionate equivalents. Three parallelgroup studies in adults (two doubling and one quadrupling; mean achieved dose of 1,695 mcg with a range of 1,420 to 2,075 mcg), involving 1,080 patients contributed data to the primary outcome. There was no significant reduction in the need for rescue oral corticosteroids when patients were randomized to the increased dose of ICS compared to the stable maintenance dose groups (OR 0.85; 95% CI, 0.58 to 1.26). Statistically, there was no significant difference in the overall risk of non-serious adverse events associated with the increased ICS dose strategy, but the wide confidence interval prevents a firm conclusion. No serious adverse events were reported. In 2011, a meta-analysis that compared two or more doses of ICS in pediatric patients (age three to 18 years) with persistent asthma was published to assess the dose-response relationship including benefits and harms of ICS in children with persistent asthma. 204 A Medline search was conducted for articles published between 1950 and August Main outcomes of this analysis included morning and evening PEF, FEV 1, asthma symptom score, beta 2 agonist use, withdrawal because of lack of efficacy, and adverse events. Meta-analyses were performed to compare moderate ( mcg ) with low ( 200 mcg beclomethasone-equivalent) doses of the ICS. Fourteen RCTs that included 5,768 asthmatic children that evaluated five different ICS were included in the analysis. The pooled standardized mean difference from six trials revealed a small but statistically significant increase of moderate over low doses in improving FEV 1 (standardized mean difference, 0.11; 95% CI, ) among children with mild-to-moderate asthma. There was no significant difference between two doses in terms of other efficacy outcomes. Local adverse events were uncommon, and there was no evidence of dose-response relationship at low-to-moderate doses. In 2011, a meta-analysis compared the relative effects of ICS compared to long-acting beta 2 -agonists (LABA) on clinical outcomes in patients with stable COPD in 5,997 patients (seven RCTs). 205 All of the trials compared ICS/LABA combination inhalers with LABA and ICS as individual components. Four of these trials included fluticasone and salmeterol mono components and the remaining three included budesonide and formoterol mono components. There was no statistically significant difference in the primary outcome, the number of patients experiencing exacerbations (odds ratio (OR) 1.22; 95% CI, 0.89 to 1.67), or the rate of exacerbations per patient year (rate ratio (RR) 0.96; 95% CI, 0.89 to 1.02) Page 35

36 between ICS and LABAs. The incidence of pneumonia, the co-primary outcome, was significantly higher among patients on ICS than on LABAs whether classified as an adverse event (OR 1.38; 95% CI, 1.1 to 1.73) or serious adverse event (Peto OR, 1.48; 95% CI, 1.13 to 1.93). In terms of the secondary outcomes analysis, mortality was higher in patients on ICS compared to patients on LABAs (Peto OR, 1.17; 95% CI, 0.97 to 1.42), although the difference was not statistically significant. Patients treated with beta 2 -agonists showed greater improvements in pre-bronchodilator FEV 1 compared to those treated with ICS (mean difference (MD) ml; 95% CI, 0.52 to 37.46). However, there were greater improvements in health-related quality of life observed in patients receiving ICS compared to those receiving long LABAs (St George's Respiratory Questionnaire (SGRQ) MD -0.74; 95% CI, to -0.06). In both cases, the differences were statistically significant but rather small in magnitude. There were no statistically significant differences between ICS and LABA in the number of hospitalizations due to exacerbations, number of mild exacerbations, PEF, dyspnea, symptoms scores, use of rescue medication, adverse events, all cause hospitalizations, or withdrawals from studies. The authors concluded that their findings support current guidelines advocating LABAs as frontline therapy for COPD, with regular inhaled corticosteroid therapy as an adjunct in patients experiencing frequent exacerbations. A Cochrane database systematic review evaluated ICS in stable COPD. 206 Fifty-five randomized, placebo-controlled studies, representing 16,154 patients, and five different ICS (budesonide, beclomethasone dipropionate, fluticasone propionate, triamcinolone acetonide, mometasone furoate) were included in the analysis. The rate of decline of FEV 1 was not blunted by the extended use (greater than six months) of ICS in COPD patients (generic inverse variance analysis: mean difference [MD] 5.8 ml/year with ICS over placebo, 95% CI to 11.88, 2,333 participants; pooled means analysis: 6.88 ml/year, 95% CI 1.8 to 11.96, 4,823 participants). However, statistically significant reductions were seen in the mean rate of exacerbations (generic inverse variance analysis: MD exacerbations per patient per year, 95% CI to -0.14, 2,586 participants; pooled means analysis: MD exacerbations per patient per year, 95% CI -0.3 to -0.08, 2,253 participants) and the rate of decline in quality of life as measured by the St. George s Respiratory Questionnaire (MD units/year, 95% CI to -0.6, 2507 participants). Conversely, increased rates of oropharyngeal candidiasis (OR 2.65, 95% CI 2.03 to 3.46, 5,586 participants) and pneumonia were observed in patients utilizing ICS. No statistically significant effect on mortality was observed (odds ratio [OR] 0.98, 95% CI 0.83 to 1.16, 8,390 participants). This review advises clinicians to balance the increased risk of adverse effects (e.g. oropharyngeal candidiasis and pneumonia), when considering the use of ICS in COPD to capture the potential benefits of decreased rates of exacerbations and quality of life decline. A separate meta-analysis looked at the comparison of ICS/LABA products to LABA alone. 207 Fourteen randomized, blinded studies enrolling 11,794 individuals met inclusion criteria for the analysis. Risk of mortality did not differ significantly between the two therapies (OR 0.92; 95% CI, 0.76 to 1.11, moderate quality). Pneumonia was more common in the ICS/LABA group as compared to LABA alone (OR 1.55; 95% CI, 1.2 to 2.01, moderate quality). The other primary outcomes, including rate of hospitalizations and risk of exacerbation, were determined to have low quality evidence by the reviewers; neither outcome demonstrated a significant difference between the two groups. SUMMARY The 2007 National Heart, Lung, and Blood Institute (NHLBI) and National Institutes of Health ( NIH) and 2015 Global Initiative for Asthma (GINA) both utilize a classification of level of asthma control to guide Page 36

37 asthma therapy and state that inhaled corticosteroids (ICS) are currently the most effective antiinflammatory medications for the treatment of persistent asthma. Bronchodilator therapy is central to symptom management in chronic obstructive pulmonary disease and the inhaled route is preferred. The GOLD guidelines recommend the addition of ICS to long-acting bronchodilator therapy, such as long-acting beta 2 -agonists, for patients with severe to very severe COPD. When used in equivalent dosages, efficacy among all inhaled corticosteroids is similar. There are differences among the agents in dosage frequency and the number of inhalations needed for each dose. Most of these agents are recommended for twice use. The exceptions to this are mometasone (Asmanex Twisthaler DPI) and fluticasone furoate (Arnuity Ellipta), which can be dosed once. Also, there are two agents that act as prodrugs, ciclesonide (Alvesco) and beclomethasone (QVAR). They are both converted either during absorption (beclomethasone) or by esterases in the lung (ciclesonide). The use of a combination long acting beta agonist and an ICS [e.g., salmeterol/fluticasone propionate (Advair), formoterol/budesonide (Symbicort), formoterol/mometasone (Dulera), fluticasone furoate/vilanterol (Breo Ellipta)] in a single inhaler is effective in the treatment of asthma and reduces asthma exacerbations. Salmeterol/fluticasone propionate (Advair), formoterol/budesonide (Symbicort), and fluticasone furoate/vilanterol (Breo Ellipta) are also indicated for the maintenance treatment of airflow obstruction in patients with COPD; formoterol/mometasone (Dulera) is not approved for this indication. Fluticasone furoate/vilanterol (Breo Ellipta) is dosed once while budesonide/formoterol (Symbicort) and fluticasone propionate/salmeterol (Advair) are dosed twice. FDA recommendations on the safe use of long-acting beta 2 -agonists in the treatment of asthma, also apply to the combination ICS/long-acting beta 2 -agonist products. The FDA recommends against the use of long-acting beta 2 -agonists without the use of an asthma controller medication such as an ICS. Also, long-acting beta 2 -agonists should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved, and used long-term only in patients whose asthma is not adequately controlled on asthma controller medications. When selecting an agent for an individual patient, consideration must be given to the characteristics of the particular delivery device and the necessary technique for its use. This is particularly important for the very young and the very old. For children under five years of age, a metered-dose inhaler (MDI) with a spacer and an optional face mask or mouthpiece may be preferable. If this is not effective, consideration could be given towards nebulizer therapy or a drypowder inhaler (DPI) as an alternative for individuals, young and old, who cannot use MDIs due to an inability to coordinate hand and press devices. Page 37

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